The present invention relates to pharmaceutical compositions, and particularly pharmaceutical compositions incorporating compounds that are capable of affecting acetylcholine levels. More particularly, the present invention relates to pharmaceutical compositions incorporating at least one component capable of inhibiting acetylcholinesterase and at least one compound capable of interacting with (e.g., activating) nicotinic cholinergic receptors (e.g., at least one agonist of specific nicotinic receptor subtypes). The present invention also relates to methods for treating a wide variety of conditions and disorders, and particularly conditions and disorders associated with dysfunction of the central and autonomic nervous systems.
Central nervous system (CNS) disorders are a type of neurological disorder. CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology. CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency. CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Lewy body diseasse (LBD), supranuclear palsy (SNP), Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313 (1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release of norepinephrine by neurons upon administration of nicotine has been reported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release of serotonin by neurons upon administration of nicotine has been reported by Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release of glutamate by neurons upon administration of nicotine has been reported by Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain disorders. See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993); Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, Decina et al., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry 21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984); Onaivi et al., Life Sci. 54(3):193 (1994); Tripathi et al., JPET 221: 91-96 (1982) and Hamon, Trends in Pharmacol. Res. 15:36.
Various nicotinic compounds have been reported as being useful for treating a variety of conditions and disorders, including various CNS disorders. See, for example, Williams et al. DN&P 7(4):205-227 (1994), Americ et al., CNS Drug Rev. 1(1):1-26 (1995), Americ et al., Exp. Opin. Invest. Drugs 5(1):79-100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997), Lin et al., J. Med. Chem. 40: 385-390 (1997), Holladay et al., J. Med. Chem 40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-80 (1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No. 5,604,231 to Smith et al. and U.S. Pat. No. 5,616,716 to Dull et al.
Various acetylcholinesterase (AChE) inhibitors have been reported as being useful for treating a variety of conditions and disorders, including various CNS disorders. AChE inhibitors limit the activity of the enzyme, acetylcholinesterase, which hydrolyzes the endogenous neurotransmitter acetylcholine (ACh); and as such, AChE inhibitors reportedly preserve existing ACh levels in patients treated therewith, and the resulting increase in extracellular ACh within the CNS reportedly restores central cholinergic hypofunction and hence improves memory and cognition. One commercially available AChE inhibitor Cognex, which is marketed as a treatment for Alzheimer's disease as capsule containing tacrine hydrochloride, available from Parke-Davis Division of Warner-Lambert Company. Another-commercially available AChE inhibitor is Aricept, which is a capsule containing donezepil hydrochloride, available from Eisai. Other reported AChE inhibitors include Amirine from Nikken Pharmaceuticals, SW-10888 from Sumitomo, MF-217 from Mediolanum Pharmaceutici-Angelini, Ro 45-5934, HP-290 from Hoesht-Russel, ENA 713 from Sandoz, Itameline from Hoesht, Metrifonate from Bayer-Wiles, Tak 177 from Takeda, CP 118.954 from Pfizer, Galanthamine from Naedheim Pharmaceuticals, ONO 1603 from Ono, Zifrosilone from Marion Merrel Dow. See, for example those AChE inhibitors set forth in Brufani et al, Alzheimer Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 171-177 (1996); Schmidt et al., Alzheimer Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 217-221 (1996); Vargas et al., Alzheimer Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 251-255 (1996); Greig et al., Alzheimer Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 231-237 (1996); and Giacobini, Alzheimer Disease: From Molecular Biology to Therapy eds. Becker et al., pp. 187-204 (1996). Such AChE inhibitors include eptastigmine, metrifonate and phenserine. However, certain AChE inhibitors have limited efficacy, are difficult to titrate, can affect liver function, are contraindicated in many disease states, and can cause side effects (e.g., hepatotoxicity, headache, myalgia, nausea/vomiting, dyspepsia, dizziness, ataxia, anorexia, and diarrhea).
It would be desirable to provide a useful method for the prevention and treatment of a condition or disorder by administering to a patient susceptible to or suffering from such a condition or disorder a therapeutic capable of effecting the ACh level within that patient. It would be highly beneficial to provide individuals suffering from certain disorders (e.g., CNS diseases) with interruption of the symptoms of those disorders by the administration of a pharmaceutical composition containing an active ingredient having nicotinic pharmacology and which has a beneficial effect (e.g., upon the functioning of the CNS), but which does not provide any significant associated side effects. It would be highly desirable to provide a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors, such as those which have the potential to affect the functioning of the CNS, but which compound when employed in an amount sufficient to affect the functioning of the CNS, does not significantly affect those receptor subtypes which have the potential to induce undesirable side effects (e.g., appreciable activity at skeletal muscle and ganglia sites).